Pharmaceutical compositions containing carvedilol and hydrochlorothiazide

ABSTRACT

A pharmaceutical combination preparation for the treatment of cardiac and cardiovascular disorders, such as hypertension, angina pectoris, cardiac insufficiency and illnesses associated therewith, contains the active substances carvedilol, or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide, or a pharmaceutically acceptable salt thereof, as well as pharmaceutically usual additives.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This is a divisional of copending application Ser. No. 09/447,872filed Nov. 23 1999.

BACKGROUND OF THE INVENTION

[0002] 1. Field

[0003] The present invention is concerned with pharmaceuticalcombination preparations that are suitable for treating cardiac andcardiovascular disorders and the illnesses associated therewith.Specifically, the present invention relates to pharmaceuticalcombination preparations containing carvedilol and hydrochlorothiazideas active substances.

[0004] 2. Description

[0005] Carvedilol, a compound of the formula:

[0006] is a β-blocker with additional α₁-blocking activity, which hasbeen commercially available for several years under the trade nameCoreg® in the United States and Dilatrend™ outside the United States.

[0007] Hydrochlorothiazide, a compound of the formula:

[0008] is a diuretic, which has been marketed for decades.

[0009] The combination of a β-blocker with a diuretic has been usedsuccessfully for treating cardiac and circulatory disorders such ashypertension, angina pectoris, cardiac insufficiency and illnessesassociated therewith. Many studies have investigated the advantages ofcombination therapy using carvedilol and hydrochlorothiazide (e.g.Widmann et al., 1990, Eur J Clin Pharmacol 38 (2):143-146; van der Doeset al., 1990, Eur J Clin Pharmacol 38 (2):147-152; McTavish et al.,1993, Drugs 45(2): 232-258). In all of these studies, the two activesubstances carvedilol and hydrochlorothiazide were sequentiallyadministered in the form of individual tablets. A fixed combination ofthe two active substances could not be realized until the presentinvention.

[0010] A combined product was not earlier developed because the twoactive substances, carvedilol and hydrochlorothiazide, have differentsolubilities and, when granulated together, gave end products withinadequate active substance release and bioavailability. Thus, it wasproblematic to provide the two active substances as a combinationpreparation, such as a tablet. An object of the invention is to providea solution to these problems.

SUMMARY OF THE INVENTION

[0011] The subject invention provides a pharmaceutical combinationpreparation containing the active substances (i) carvedilol, or apharmaceutically acceptable salt thereof, and (ii) hydrochlorothiazide,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable additive.

[0012] The preferred weight ratio of (i) hydrochlorothiazide, or apharmaceutically acceptable salt thereof, to (ii) carvedilol, or apharmaceutically acceptable salt thereof, is between about 1:0.5 andabout 1:10. Typically, the preparation is in dosage form containing (i)about 10 mg to about 50 mg of carvedilol, or a pharmaceuticallyacceptable salt thereof, and (ii) about 5 mg to about 30 mg ofhydrochlorothiazide, or a pharmaceutically acceptable salt thereof. Theacceptable additive includes binders, disintegrants, glidants,adsorption agents, separating agents, fillers, and carriers. A morepreferred pharmaceutical combination preparation contains about 0 weight% to about 50 weight % lactose, about 0 weight % to about 50 weight %saccharose, about 0 weight % to about 10 weight % magnesium stearate,about 0 weight % to about 30 weight % cellulose, about 0 weight % toabout 10 weight % polyvinylpyrrolidone, about 0 weight to about 10weight % polymeric cellulose compounds, about 0 weight % to about 10weight % highly dispersed silicon dioxide and about 0 weight % to about20 weight % cross-linked polyvinylpyrrolidone. Most preferably, thepreparation is in solid dosage form.

[0013] The subject invention also provides method for treating ofcardiac and circulatory disorders which comprises administering aneffective amount of a pharmaceutical combination preparation in dosageform containing the active substances (i) carvedilol, or apharmaceutically acceptable salt thereof, and (ii) hydrochlorothiazide,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable additive.

[0014] Another aspect of the subject invention is a process forproducing a solid dosage form pharmaceutical combination preparationcontaining carvedilol, or a pharmaceutically acceptable salt thereof,and hydrochlorothiazide, or a pharmaceutically acceptable salt thereof.The process comprises (i) forming a press mass containing a carvedilol,or pharmaceutically acceptable salt thereof, granulate and ahydrochlorothiazide carvedilol, or pharmaceutically acceptable saltthereof, granulate and (ii) compressing the press mass to form the soliddosage form pharmaceutical combination preparation. The two granulateseach having a granulate moisture content between about 6% and about 20%and a bulk density between about 0.1 g/ml and about 1.5 g/ml. Thegranuate moisture content and the bulk density of the two granulates donot vary from each other by more than about 30%.

[0015] The granulate moisture content of the carvedilol, orpharmaceutically acceptable salt thereof, granulate and thehydrochlorothiazide, or pharmaceutically acceptable salt thereof,granulate is preferably between about 10% and about 15%. The bulkdensity of both the carvedilol, or pharmaceutically acceptable saltthereof, granulate and the hydrochlorothiazide, or pharmaceuticallyacceptable salt thereof, granulate is preferably between about 0.4 g/mland about 0.75 g/ml. Compressing is generally accomplished using atablet press to form tablets. The process can further comprise coatingthe solid dosage form with a pharmaceutically acceptable aqueous filmsuspension. The coating of the solid dosage form is typically firstperformed at a rate of about 30 g to about 50 g of film suspension perminute during the first about 30 minutes to about 70 minutes and thenperformed at a rate of about 60 g to about 90 g of film suspension perminute until the film coating has finished. Pharmaceutically acceptablesolid dosage form combination preparations prepared using the describedprocess are also part of the invention. The amount of the disintegrantin the dosage form is typically at least 5 weight %.

[0016] Another aspect of the invention is a light-protecting filmsuspension for use in coating solid dosage form pharmaceuticalpreparations. This light-protecting film preferably comprises: about 10weight % to about 50 weight % poly(ethyl acrylate, methyl acrylate) 2:1,800,000; about 1 weight % to about 10 weight % sodium citrate; about 1weight % to about 25 weight % methylhydroxypropylcellulose; about 0weight % to about 20 weight % macrogol 10,000; about 5 weight % to about40 weight % talc; about 2 weight % to about 25 weight % titaniumdioxide; about 0 weight % to about 10 weight % indigocarmine colorlacquer; about 0 weight % to about 2 weight % polysorbate; and about 0weight % to about 1.0 weight % dimethicone.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention will now be described in terms of itspreferred embodiments. These embodiments are set forth to aid inunderstanding the invention but are not to be considered limiting.

[0018] The present invention is concerned with pharmaceuticalcombination preparations containing the active substances carvedilol, ora pharmaceutically acceptable salt thereof, and hydrochlorothiazide, ora pharmaceutically acceptable salt thereof, as well as pharmaceuticallyusual additives. Moreover, the present invention is concerned with theuse of this combination preparation for the treatment of cardiac andcirculatory disorders such as hypertension, angina pectoris, cardiacinsufficiency and illnesses associated therewith.

[0019] The term “pharmaceutical combination preparation” refers to apharmaceutically acceptable dosage form which simultaneously containstwo or more active substances.

[0020] Pharmaceutically acceptable salts of the compounds of theformulas (I) and (II) include alkali salts, such as Na or K salts,alkaline earth metal salts, such as Ca and Mg salts, as well as saltswith organic or inorganic acids, such as, for example, hydrochloricacid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid,citric acid, formic acid, maleic acid, acetic acid, succinic acid,tartaric acid, methanesulphonic acid or toluenesulphonic acid, which arenon-toxic for living organisms.

[0021] The phrase “drying loss” of granulates refers to the gravimetricdetermination of the weight difference between original granulate andthe granulate dried to constant weight. Drying can be effected, forexample, in a drying oven at elevated temperatures, with an infra-redlamp, with a microwave apparatus, with a hot air blower, etc.

[0022] Measurement of the granulate moisture in the presentspecification was effected with a SUPERMATIC rapid hygrometer from thefirm Foss Electric (accuracy ±0.25%). The measurement principle is basedon the measurement of the dielectric constants of the measured material.A sample amount of 250 g was used.

[0023] In a preferred embodiment of the combination preparation inaccordance with the invention the weight ratio of hydrochlorothiazide ora pharmaceutically acceptable salt thereof to carvedilol or apharmaceutically acceptable salt thereof lies between 1:0.5 and 1:10,preferably between 1:0.5 and 1:5, especially at 1:2.

[0024] A preferred combination preparation in accordance with theinvention contains between 10 mg and 50 mg, preferably 25 mg, ofcarvedilol or a pharmaceutically acceptable salt thereof and between 5mg and 30 mg, preferably 12.5 mg, of hydrochlorothiazide or apharmaceutically acceptable salt thereof in an oral dosage form.

[0025] The combination preparations in accordance with the invention maycontain additives such as binders, plasticizers, diluents, carriers,glidants, antistatics, adsorbing agents, separating agents, dispersants,drageeing lacquers, de-foamers, film formers, emulsifiers, disintegrantsand fillers in the tablets and/or the coating. Tablets or granulates,for example, can contain flavor-improving additives as well assubstances usually used as preservatives, stabilizers,moisture-retainers and emulsifiers, salts for varying the osmoticpressure, buffers and other additives.

[0026] The additives mentioned above can comprise organic or inorganicsubstances, e.g. water, sugar, salts, acids, bases, alcohols, organicpolymeric compounds, and the like. Lactose, saccharose, magnesiumstearate, various celluloses and substituted celluloses, polymericcellulose compounds, highly dispersed silicon dioxide, maize starch,talc and various polymeric polyvinylpyrrolidone compounds are preferredadditives. For example, polyvinylpyrrolidones, which are notcross-linked, with a molecular weight of 8,000 to 630,000, preferably25,000, and cross-linked polyvinylpyrrolidones with a molecular weightgreater than 1,000,000 can be used. It is a prerequisite that alladditives used in the production are non-toxic and advantageously do notalter the bioavailability of the active substances.

[0027] Solid dosage forms which contain about 0-50 weight % lactose,about 0-50 weight % saccharose, about 0-10 weight % magnesium stearate,about 0-30 weight % cellulose, about 0-10 weight % polyvinylpyrrolidone,about 0-10 weight % polymeric cellulose compounds, about 0-10 weight %highly dispersed silicon dioxide, and about 0-20 weight % cross-linkedpolyvinylpyrrolidone as additives are especially preferred.

[0028] A combination preparation in accordance with the invention whichcontains about 25 mg of carvedilol, about 12.5 mg ofhydrochlorothiazide, about 25.0 mg of saccharose, about 28.06 mg oflactose, about 1.78 mg of polyvinylpyrrolidone, about 20.17 mg ofcross-linked polyvinylpyrrolidone, about 10-0 mg of microcrystallinecellulose, about 5.32 mg of highyl dispersed silicon dioxide and about2.17 mg of magnesium stearate per 130 mg solid dosage form is especiallypreferred.

[0029] Further, it has surprisingly been found that the process used forthe production of the combination preparations permits the two activesubstance granulates to be pressed to a stable tablet in one operation.

[0030] The active substances and additives required for the productionof the combination preparation in accordance with the invention areknown (Carvedilol: EP 0004920; hydrochlorothiazide: PharmaceuticallyActive Substances; Syntheses, Patents, Uses, A. Kleemann et al., 2^(nd)Edition, published by Georg Thieme, 1982, page 469) or are commerciallyavailable or can be produced in accordance with known methods.

[0031] The process for the production of the combination preparation inaccordance with the invention can comprise the steps describedhereinafter, but is not limited to these individual steps:

[0032] a) the production of a carvedilol granulate;

[0033] b) the production of a hydrochlorothiazide granulate;

[0034] c) the processing of a carvedilol granulate and ahydrochlorothiazide granulate to a press mass, with the two granulateseach having a granulate moisture content between 6 and 20% and a bulkdensity between 0.1 and 1.5 g/ml and the granuate moisture content andthe bulk density of the two granulates in each case not varying from oneanother by more than 30%, preferably 20%;

[0035] d) the production of a solid dosage form, preferably a tablet,from the press mass obtained under c).

[0036] The carvedilol granulate is preferably produced by fluidized bedgranulation, the hydrochlorothiazide granulate preferably by granulationin a high speed mixer-granulator (e.g. DIOSNA P 450).

[0037] The granulate moisture content of the carvedilol granulate and ofthe hydrochlorothiazide granulate preferably lies between 10 and 15%.

[0038] The bulk density of the two granulates preferably lies between0.4 and 0.75 g/ml.

[0039] In a particular embodiment the combination peparation, as well asa carvedilol preparation alone, can be provided with a light-protectingfilm.

[0040] As carvedilol is an active substance which is particularlysensitive to light, a distinct brown coloration of the active substancecan occur not only in the case of the pure active substance but also inthe case of carvedilol-containing medicaments in different dosages whenthese forms are exposed to light.

[0041] Under a “light-protecting film” there is to be understood acoating based on an aqueous film suspension applied to the dosage form,preferably by spraying.

[0042] The film suspension preferably contains about 10-50 weight %poly(ethyl acrylate, methyl acrylate) 2:1, 800,000, about 1-10 weight %sodium citrate, about 1-25 weight % methylhydroxypropylcellulose, about0-20 weight % macrogol 10,000, about 5-40 weight % talc, about 2-25weight % titanium dioxide, about 0-10 weight % indigocarmine colorlacquer, about 0-2 weight % polysorbate and about 0-1.0 weight %dimethicone.

[0043] A light-protecting film which contains about 2.348 mg ofpoly(ethyl acrylate, methyl acrylate) 2:1, 800,000, about 0.308 mg ofsodium citrate, about 1.018 mg of methylhydroxypropylcellulose, about0.644 mg of macrogol 10,000, about 1.624 mg of talc, about 0.950 mg oftitanium dioxide, about 0.170 mg of indigocarmine color lacquer, about0.034 mg of polysorbate and about 0.004 mg of dimethicone per 7 g offilm suspension is especially preferred.

[0044] All polysorbates (polyoxyethylene derivatives) of the polysorbate20 to polysorbate 85 type, preferably polysorbate 80, can be used forthe film coating.

[0045] Although the light-protecting film described above is used forthe film coating of oral dosage forms, such as e.g. tablets, containingcarvedilol, not only as a single but also as a combination preparation,it is, of course, also suitable for tablets containing otherlight-sensitive active substances.

[0046] In a further embodiment the invention also includes a process forthe application of a light-protecting film.

[0047] Since carvedilol is not very water soluble, carvedilol-containingmedicaments typically contain an especially high content of disintegrant(15-20 weight % cross-linked polyvinylpyrrolidone). It is known to theskilled artisan that the direct application of an aqueous suspension toa tablet with a disintegrant content of more than 5 weight % in oneoperation is typically associated with problems because a reaction canoccur between water from the film suspension and disintegrant from thetablet, which softens the surface of the tablet. It has now surprisinglybeen found that by the inventive process described below, an aqueoussuspension, preferably an aqueous light-protecting suspension, such asthe aforementioned film suspension, can be applied in one operation to atablet having a disintegrant content of more than 5%.

[0048] The specific procedure at the beginning of the film coating iscritical for the process: The spray rate must be so low at the beginningon the one hand to permit the formation of a film on the tablet surfaceand on the other hand to remove the water of the film suspension asrapidly as possible from the tablet surface. This procedure isadditionally assisted by the supply of large amounts of air and a highair supply temperature in the drageeing kettle. As soon as this criticalphase of the film coating has been completed, i.e. a thin film hasformed over the entire tablet, the spray rate can be increased to anextent which is usual in the case of conventional film coatings. Thefilm coating can be carried out to the end using this increased sprayrate. The aforementioned inventive film coating procedure is alsofacilitated and assisted by the composition of the film suspension.

[0049] The tablets to be film coated are added to a drageeing kettle(e.g. a 50 kg drageeing kettle from the firm BRUCKS, Model XI) and filmcoated with the light-protecting suspension (film coating e.g. with abinary spray nozzle from the firm WALTHER, PILOT type, Model WA).

[0050] The following data refer to a film coating using theaforementioned drageeing kettle and binary spray nozzles. However, thesevalues can be readily varied by the artisan depending on the equipmentused.

[0051] During the first 30 to 70, preferably 50, minutes the filmcoating of the solid dosage form is effected with 30 to 50 g, preferablywith 40 g, of film suspension per minute and subsequently until the filmcoating has finished with 60 to 90 g, preferably with 74 g, of filmsuspension per minute. In a process variant, after 40 to 60 minutes, thespray rate can also be increased continuously to the maximum value of 60to 90 g per minute.

[0052] The film coating process described above can be used for the filmcoating of any pharmaceutically acceptable solid dosage form, such astablets, with a disintegrant content of more than 5%. Thus, for example,a pharmaceutically acceptable solid dosage form containing 0-20 weight %carvedilol, 0-50 weight % lactose, 0-50 weight % saccharose, 0-10 weightmagnesium stearate, 0-30 weight cellulose, 0-10 weightpolyvinylpyrrolidone, 0-10 weight highly dispersed silicon dioxide and0-20 weight cross-linked polyvinylpyrrolidone can also be coated with apharmaceutically acceptable aqueous film suspension. The combinationpreparations produced and film coated according to the process inaccordance with the invention have a surprisingly long stability.

[0053] Oral administration is the preferred form of administration forthe combination preparation in accordance with the invention. Preferreddosage forms include tablets, capsules and dragees. However, tablets aremost preferred. The dosage in which the combination preparation inaccordance with the invention is administered depends on the age and therequirements of the patient and on the route of administration. Ingeneral, dosages of about 10-50 mg of carvedilol and about 5-30 mg ofhydrochlorothiazide per day come into consideration.

[0054] The following Examples are intended to illustrate the preferredembodiments of the present invention, without limiting them.

EXAMPLE 1

[0055] Production of a Carvedilol Granulate

[0056] a) Production of the Suspension

[0057] 64,500 g of purified water are placed in a kettle and 15,000 g ofsieved lactose D80, 7,500 g of sieved saccharose and 1,500 g ofpolyvinylpyrrolidone 25,000 (e.g. Kollidon 25) are added thereto anddissolved while stirring for 30 minutes. Subsequently, 3,000 g of highlydispersed silicon dioxide (e.g. Aerosil 200) and 37,500 g of finelycrystalline carvedilol are added to the above solution and stirred for30 minutes until a homogeneous suspension is produced. The suspension ispumped over a colloid mill and a hand sieve into a different container.The suspension is stirred continuously until the fluidized bedgranulation has finished in order to prevent settling.

[0058] b) Fluidized Bed Granulation

[0059] 30,000 g of finely ground saccharose and 15,000 g of cross-linkedpolyvinylpyrrolidone (e.g. Plasdone XL) are placed in the pan of thefluidized bed granulator (e.g. GLATT-WSG 150). The suspension obtainedunder a) is introduced using a tube pump (internal tube diameter: 10 mm)via a 2.2 mm binary nozzle (1^(st) material: suspension; 2^(nd)material: purified compressed air of 6 bar). The spray granulation takesplace with an air supply temperature of about 80° C. and a producttemperature of about 34° C. to 37° C. The moisture content of the spentair amounts to 50 to 70% of the relative humidity, the spraying timeamounts to about 120 minutes.

[0060] c) Sieving

[0061] After the fluidized bed granulation the granulate is passedthrough a sieve with a mesh size of 1.2 mm.

[0062] d) Final Mixing

[0063] 8,250 g of cross-linked polyvinylpyrrolidone (e.g. Plasdone XL)and 3,000 g of highly dispersed silicon dioxide (e.g. Aerosil 200) arepassed through a sieve with a mesh size of 1.2 mm and homogenized withthe granulate in a mixer (e.g. a plowshare mixer from the firm LÖDIGE).Then, 2,250 g of magnesium stearate are passed through a sieve with amesh size of 1.2 mm and the sieved magnesium stearate is mixed brieflywith the granulate and the granulate yield is established (targetweight: 123,000 g). Subsequently, the IPC values (IPC in processcontrol) of the final mixture are determined, with it being necessary toachieve the following target values: Granulate moisture 11.5-12.5%Drying loss (microwave)  2.0--3.0% Bulk density 0.50-0.65 g/ml

EXAMPLE 2

[0064] Production of a Hydrochlorothiazide Granulate

[0065] a) Production of the Granulation Solution

[0066] 1,040 g of polyvinylpyrrolidone 25,000 (e.g. Kollidon 25 having amean average mol wt of approximately 25,000) are dissolved in 9,620 g ofwater while stirring.

[0067] b) Granulation of the Active Substance and Additives

[0068] 19,500 g of hydrochlorothiazide and 28,340 g of lactose are mixedin a mixer-granulator (e.g. DIOSNA) for 4 minutes. Thereafter, 10,660 gof the granulation solution from a) are sprayed into the mixer with aspray pressure of 2 bar and granulated in the mixer-granulator for 5minutes. The mist granulate is dried to a defined final moisture contentat an air inlet temperature of 75° C.

[0069] c) Granulate Sieving

[0070] The dried granulate from b) is passed through a pharma sieve witha mesh size of 1.25 mm [and] subsequently the granulate moisture isdetermined. The target value lies at 9.5 to 11.0%. Subsequently, thegranulate weight is determined (target weight: 74,880 g).

[0071] d) Production of the Final Mixture

[0072] 15,600 g of microcrystalline cellulose together with 7,280 g ofcross-linked polyvinylpyrrolidone (e.g. Plasdone XL), 2,080 g of highlydispersed silicon dioxide (e.g. Aerosil 200) and 1,040 g of magnesiumstearate are passed through a pharma sieve with a mesh size of 1.25 mm.This sieved material and the sieved granulate from c) are added to apharma mixer and mixed for 30 seconds. The finished mixture isdischarged into a pharma container and the yield is determined.Subsequently, the IPC values of the final mixture are determined, withit being necessary to achieve the following target values: Granulatemoisture 10.0-11.0% Drying loss (microwave)  1.5-2.5% Bulk density0.50-0.65 g/ml

EXAMPLE 3

[0073] Production of a Carvedilol-hydrochlorothiazide Press Mass

[0074] a) Mixing of the Press Mass

[0075] 70,340 g of hydrochlorothiazide granulate and 120,160 g ofcarvedilol granulate are placed in a suitable pharma mixer (e.g.plowshare mixer LODIGE) and homogeneously mixed. The mixing time amountsto 3 minutes. The finished mixture is filled into an air-tight containerthrough which light cannot pass and the yield is determined (targetweight: 19,500 g). Subsequently, the IPC values of the final mixture aredetermined, with it being necessary to achieve the following targetvalues: Granulate moisture 11.0-12.0% Drying loss (microwave)  2.0-3.0%Bulk density 0.50-0.65 g/ml

EXAMPLE 4

[0076] Production of the Tablets

[0077] The press mass is pressed using a computer-controlled highperformance rotary tablet press (e.g. KILIAN TX 40 with automaticpressing force control as well as regulation and control of the tabletweight) to tablets, which are stored in container through which lightcannot pass.

EXAMPLE 5

[0078] Protection of Carvedilol-containing Medicaments from Light byFilm Coating

[0079] a) Production of the Film Suspension:

[0080] 364 g of Pharmacoat (=methylhydroxypropylcellulose), 230 g ofmacrogol 10,000 (polyethylene glycol, approximate average mol wt of10,000), 110 g of sodium citrate, 979 g of talc, 339 g of titaniumdioxide, 12 g of Tween (polysorbate 80), 61 g of indigocarmine colorlacquer and 4 g of dimethicone are dissolved in 6,900 g of hot water(30-60° C.) while stirring. The homogeneous solution is passed twicethrough a colloid mill. 401 g of Eudragit NE 30 D are added immediatelybefore the film coating.

[0081] b) Film Coating:

[0082] 60-70 kg of dust-free tablets from Example 3 are placed in adrageeing kettle and film coated with the suspension from a). The coresare sprayed from above, with the distance of the spray nozzle from thecore bed being about 60-70 cm. A binary nozzle (compressed air/liquid)with a diameter of 1.8 mm is used for this purpose. The sprayed airpressure (purified compressed air) amounts to 3 bar, the temperature ofthe input air amounts to 70° C., the amount of input air amounts to350-500 m³/h and the amount of spent air amounts to 700-1,000 m³/h. Atube pump is used to introduce the liquid, with the PVC pipe having anexternal diameter of 8 mm and an internal diameter of 4 mm. The pumpspeed is 10 rpm during the first 50 minutes and is subsequently 25 rpm.Based on the film suspension, the pump speed is 40 g suspension/minuteduring the first 50 minutes and subsequently (about a further 100minutes) it is increased stepwise up to 74 g suspension/minute. Therotation velocity of the kettle is 12 rpm during the first 50 minutesand is thereafter 18 rpm. The kettle inclination lies at 60 degrees.

EXAMPLE A

[0083] Tablets containing the following ingredients can be producedaccording to the process described above: Active substances Carvedilol25.000 mg Hydrochiorothiazide 12.500 mg Additives Saccharose Ph.Eur.25.000 mg Lactose 1 H₂O Ph.Eur. 28.060 mg Polyvinylpyrrolidone 25,000Ph.Eur. 1.780 mg Cross-linked polyvinylpyrrolidone NF 20.170 mgMicrocrystalline cellulose Ph.Eur. 10.000 mg Highly dispersed silicondioxide Ph.Eur. 5.320 mg Magnesium stearate Ph.Eur. 2.170 mg Filmcoating Poly(ethyl acrylate, methyl acrylate) 2:1, 2.248 mg 800,000average mol wt Sodium citrate Ph.Eur. 0.308 mgMethylhydroxypropylcellulose Ph.Eur. 1.018 mg Macrogol 10,000 0.644 mgTalc Ph.Eur. 1.624 mg Titanium dioxide Ph.Eur. 0.950 mg Indigocarminecolor lacquer 0.170 mg Polysorbate 80 PhiEur. 0.034 mg Dimethicone 0.004mg

[0084] Upon reading the present specification, various alternativeembodiments will become obvious to the skilled artisan. Theseembodiments are to be considered within the scope and spirit of theinvention, which is only to be limited by the claims that follow andtheir equivalents.

What is claimed is:
 1. A tablet which comprises (i) carvedilol or apharmaceutically acceptable salt thereof, (ii) hydrochlorothiazide or apharmaceutically acceptable salt thereof, and (iii) at least onepharmaceutically acceptable additive.
 2. The tablet of claim 1, whereinthe weight ratio of to (i) hydrochlorothiazide or a pharmaceuticallyacceptable salt thereof, to (ii) carvedilol or a pharmaceuticallyacceptable salt thereof, is between about 1:0.5 and about 1:10.
 3. Thetablet of claim 1, wherein the tablet comprises (i) about 10 mg to about50 mg of carvedilol or a pharmaceutically acceptable salt thereof, and(ii) about 5 mg to about 30 mg hydrochlorothiazide or a pharmaceuticallyacceptable salt thereof.
 4. The tablet of claim 1, wherein the at leastone pharmaceutically acceptable additive comprises a binder,disintegrant, glidant, adsorption agent, separating agent, filler, orcarrier.
 5. The tablet of claim 1, wherein the tablet comprises fromabout 0% to about 50 % by weight lactose, from about 0% to about 50% byweight saccharose, from about 0% to about 10% by weight magnesiumstearate, from about 0% to about 30% by weight cellulose, from about 0%to about 10% by weight polyvinylpyrrolidone, from about 0% to about 10%by weight polymeric cellulose compounds, from about 0% to about 10% byweight silicon dioxide, and from about 0% to about 20% by weightcross-linked polyvinylpyrrolidone.
 6. The tablet of claim 5, wherein thetablet comprises about 25 mg carvedilol and about 12.5 mghydrochlorothiazide.
 7. The tablet of claim 6, wherein the tabletcomprises about 25 mg carvedilol, about 12.5 mg hydrochlorothiazide,about 28.06 mg lactose monohydrate, about 25 mg saccharose, about 2.17mg magnesium stearate, about 10 mg microcrystalline cellulose, about1.78 mg polyvinylpyrrolidone (25,000), about 5.32 mg silicon dioxide,and about 20.17 mg cross-linked polyvinylpyrrolidone.